The neber approach to 2-(tetrazol-5-yl)-2 H -azirines

Article abstract of DOI:10.1021/jo4006552

The synthesis of 2-(tetrazol-5-yl)-2H-azirines is reported for the first time. Using the Neber approach, β-ketoxime-1H-tetrazoles were converted into the target 2H-azirines bearing phenyl, furan-2-yl, thiophen-2-yl, or pyrrol-2-yl substituents at C-3. It was demonstrated that the alkaloid-mediated Neber reaction allows the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines.

Full text of DOI:10.1021/jo4006552

Article
pubs.acs.org/joc
The Neber Approach to 2‑(Tetrazol-5-yl)‑2H‑Azirines
Ana Lucia Cardoso,† Lourdes Gimeno,† Americo Lemos,‡ Francisco Palacios,§
́
́
and Teresa M. V. D. Pinho e Melo*,†
†Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
‡CIQA, FCT, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
§Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, Paseo de la Universidad 7, 01006
Vitoria, Spain
S
* Supporting Information
ABSTRACT: The synthesis of 2-(tetrazol-5-yl)-2H-azirines is
reported for the first time. Using the Neber approach, β-
ketoxime-1H-tetrazoles were converted into the target 2H-
azirines bearing phenyl, furan-2-yl, thiophen-2-yl, or pyrrol-2-yl
substituents at C-3. It was demonstrated that the alkaloid-
mediated Neber reaction allows the asymmetric synthesis of 2-
(tetrazol-5-yl)-2H-azirines.
fact, the Neber rearrangement of β-ketoxime tosylates, derived
from 3-oxocarboxylic acids, mediated by Cinchona alkaloids of β-
ketoxime tosylates, afforded optically enriched 2H-azirines.5c−e
The same strategy was applied to the synthesis of chiral 2-
phosphinyl-2H-azirines5f and alkyl- and arylazirines carrying
phosphonate groups,5g being the asymmetry attributed to a
strong hydrogen bond formed between the base hydroxyl group
and one of the SO functionalities of the ketoxime. The
enantioselective Neber reaction of β-ketoxime sulfonates
catalyzed by a bifunctional chiral thiourea has also been
reported.5h
It is well-established that 5-substituted 1H-tetrazoles are
effective bioisosteres of carboxylic acids, with similar acidities, but
higher lipophilicities and metabolic stability.6 In fact, several
literature works report the enhanced biological activity and
metabolical stability of compounds in which the carboxylic group
has been substituted by tetrazole. Thus, the tetrazole ring has
been successfully incorporated into pharmacological drug
formulations, namely, cardiovascular or hypertension drugs.
Furthermore 1,5-disubstituted tetrazoles are conformational
mimics of cis blocked peptide bonds, like those found in a wide
variety of biologically important peptides.7 Thus, in drug design,
a strategy to find new lead compounds is to explore the carboxylic
acid/tetrazole bioisosterism.8
INTRODUCTION
■
2H-Azirines are the smallest unsaturated nitrogen heterocyclic
systems with two carbon atoms and an imine bond. The rich and
quite high chemical reactivity of these strained heterocycles
makes them versatile building blocks for organic synthesis.1
Chiral derivatives bearing a carboxylic acid or an ester group at C-
2 are of particular interest due to their biological behavior. In fact,
naturally occurring azirinomycin (1), isolated from Streptomyces
aureus, and its methyl ester exhibit antibiotic activity.2 Moreover,
(-)-dysidazirine (2), isolated from Dysidea fragilis, shows potent
antifungal activity against Candida albicans and Saccharomyces
cerevisiae.3 Therefore, the development of new asymmetric
syntheses of 2H-azirine-2-carboxylates has attracted significant
attention.
Chiral 2H-azirines have been prepared by the elimination
reaction of N-substituted aziridines, namely, dehydrochlorina-
tion of N-chloroaziridines,4a Swern oxidation of aziridines4b and
elimination from N-sulphynilaziridines.4c It has been reported
that the dehydrochlorination of methyl 2-chloroaziridine-2-
carboxylates generates enantiopure 2-substituted 2H-azirine-3-
carboxylate, which was not isolated but could be trapped by
Diels−Alder reaction with cyclopentadiene.4d These interesting
methods involve, nevertheless, the use of high enantiopure
aziridine esters as starting materials.
We developed a general route to 2-halo-2H-azirines starting
from haloazidoalkenes9 and became, recently, interested in the
development of synthetic routes to functionalized 5-(sub-
stituted)-1H-tetrazoles.10 The hetero-Diels−Alder reaction of
3-(1H-tetrazol-5-yl)-1,2-diaza-1,3-butadienes and 3-(1H-tetra-
zol-5-yl)nitrosoalkenes was explored, giving access to a diversity
A different approach to chiral 2H-azirines consisting of an
Received: April 17, 2013
Published: June 21, 2013
alkaloid-mediated Neber reaction has also been described.5 In
© 2013 American Chemical Society
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of tetrahydro-1,2-oxazines, tetrahydro-pyridazines, open-chain
oximes, and hydrazones bearing the tetrazole moiety.
Herein, bringing together our interest in the chemistry of small
ring heterocycles and tetrazoles, we report the synthesis of novel
2-(tetrazol-5-yl)-2H-azirines, isosteres of 2H-azirine-2-carbox-
ylates. The target three-membered heterocyclic compounds can
be particularly interesting as building blocks for the synthesis of
new 5-substituted tetrazoles. The strategy outlined was to
explore the Neber reaction of β-ketoxime tetrazole derivatives
(Scheme 1).
(entry 3). This result is in agreement with the reactivity
previously observed for alkyl nitriles, which require very high
temperatures, achieved by using sealed glass pressure reactors.14
In consonance with this observation, the thermolysis of nitrile 3a
at 140 °C for 24 h in a sealed tube led to an improvement,
allowing the isolation of 1H-tetrazole 4a in 48% yield (entry 4).
Furthermore, the increase of the reaction time to 36 h resulted in
the synthesis of β-keto-1H-tetrazole 4a in 77% yield (entry 5).
Similar efficiency was observed when β-ketonitrile 3a was
subjected to sealed tube thermolysis at 170 °C for 24 h (entry 6).
The same synthetic methodology was applied in the synthesis of
1H-tetrazoles 4b−4d (entries 7−12). Carrying out the reaction
for 24 h yields between 54% and 85% were obtained. However,
these yields were significantly improved increasing the reaction
time to 36 h. Under these conditions, 1H-tetrazoles 4b, 4c, and
4d were obtained in 72, 66, and 94% yield, respectively (entries 8,
10, and 12). Because of the low pKa of 1H-tetrazoles (ca. 3−5)
and their highly crystalline nature, it is possible, by the simple
acidification of alkaline aqueous solutions of β-keto-1H-
tetrazoles 4a−4d, to precipitate these compounds in pure form.
In the case of β-ketonitrile 3e, the conversion into the
corresponding 1H-tetrazole 4e was not so efficient (entry 13).
After heating in a sealed tube at 140 °C for 3 h, the reaction was
stopped, since a dark precipitate was formed. Nevertheless, 1H-
tetrazole 4e could be isolated in 44% yield, obtained in pure form
by crystallization of the crude product.
As an initial approach, we decided to explore the possibility of
using ketoxime tosylates of unprotected β-keto-1H-tetrazoles in
the synthesis of 2H-azirines. Ketoximes 5a and 5c were obtained
in good yield by the reaction of the corresponding β-keto-1H-
tetrazoles with hydroxylamine hydrochloride in EtOH/Py
(Scheme 3). However, attempts to form the azirine from these
tetrazoles via in situ tosylation in the presence of NEt3 failed,
leading only to degradation products. Therefore, we could
conclude that the N-protection of the 5-substituted-tetrazoles 4
was necessary so that they could be used as 2H-azirine
precursors.
Scheme 1. Synthetic Strategy for the Synthesis of 2-(1H-
Tetrazol-5-yl)-2H-azirines
RESULTS AND DISCUSSION
■
Nitrile 3a was prepared in high yield (90%) following a known
synthetic procedure based on the acylation of nitrile anions with
ethyl esters.11 We were pleased to observe that the same
approach could be applied to the synthesis of 3-oxo-3-(thiophen-
2-yl)propanenitrile (3c), although, in this case, a longer reaction
time was required (24 h), leading to the target compound in 70%
yield. Cyanoacetylation of 1H-indole and 1H-pyrrole was also
carried out by reacting these heterocycles with cyanoacetic acid
and acetic anhydride, affording the corresponding β-ketonitriles
3d and 3e in 82% and 75% yield, respectively (Scheme 2).12
The conversion of nitriles 3 into the corresponding 1H-
tetrazole derivatives was carried out by reaction with an azide
source under Lewis acid catalysis6,13,14 (Scheme 2 and Table 1).
Nitrile 3a reacted with aluminum azide, generated in situ by
treatment of aluminum chloride with sodium azide in refluxing
THF, to give 1H-tetrazole 4a in 73% yield as previously
described13c (Table 1, entry 1). However, when we tried to
extend this method to other nitriles, the results were very
disappointing. In fact, under these reaction conditions, β-keto-
1H-tetrazole 4b could only be isolated in very low yield from the
commercially available β-ketonitrile 3b (Table 1, entry 2). Thus,
the approach to 5-substituted 1H-tetrazoles reported by
Sharpless et al.14 involving the reaction of nitriles with sodium
azide and zinc bromide in water was explored. Initially, the
reactivity of nitrile 3a was studied under different reaction
conditions. Carrying out the reaction under reflux for 24 h, the
corresponding 1H-tetrazole 4a was isolated in only 20% yield
The triphenylmethyl group (Tr) was initially selected as the
protecting group since it is known that the tritylation of 5-
substituted tetrazoles usually proceeds selectively at the 2-
position of the tetrazole ring and deprotection can be achieved
under mild reaction conditions.6,15−17 Following a reported
procedure,15 we carried out the reaction of 1H-tetrazole 4a with
triphenylmethyl chloride in a mixture of toluene and aqueous
sodium hydroxide solution, at room temperature for 4 h.
However, no evidence for the N-protected derivative was
observed. Since phase-transfer catalysis is often used,16 the
tritylation was also attempted under these conditions, but the
Scheme 2. Synthesis of β-Keto-1H-tetrazoles
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a
Table 1. Synthesis of 5-Substituted 1H-Tetrazoles from β-Ketonitriles
entry
β-ketonitrile
reaction conditions
Method A
isolated yield of 4 (%)
1
2
3a
3b
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3e
73
12
20
48
77
76
54
72
58
66
85
94
44
Method A
3
Method B, reflux, 24 h
4
Method B, sealed tube, 140 °C, 24 h
Method B, sealed tube, 140 °C, 36 h
Method B, sealed tube, 170 °C, 24 h
Method B, sealed tube, 140 °C, 24 h
Method B, sealed tube, 140 °C, 36 h
Method B, sealed tube, 140 °C, 24 h
Method B, sealed tube, 140 °C, 36 h
Method B, sealed tube, 140 °C, 24 h
Method B, sealed tube, 140 °C, 36 h
Method B, sealed tube, 140 °C, 3 h
5
6
7
8
9
10
11
12
13
a
Method A: nitrile (1 equiv), NaN3 (4.5 equiv), AlCl3 (1.1 equiv), THF, reflux, 5 h. Method B: nitrile (1 equiv), NaN3 (1.1 equiv), ZnBr2 (1 equiv),
H2O/iPrOH (10% v:v).
tetrazoles 4c and 4e was accomplished, leading to the desired
products in high yields and good selectivities (entries 2 and 3).
Because the Neber rearrangement of β-ketoxime tosylates
derived from N-trityl-tetrazole could be hampered due to the
presence of the bulky trityl group, we decided to carry out the
protection with less bulkier groups that could also be easily
removed later on. Reaction of β-keto-1H-tetrazole 4a with benzyl
chloride in the presence of triethylamine, in THF at 40 °C for 1 h,
gave the corresponding benzyl derivatives 6d and 7d as a 1:1
mixture in low yield (28%). However, using benzyl bromide as
the N-protecting reagent, the target compounds could be
obtained in good yield (71%), although in a 1:1 ratio of 1,5- and
2,5-disubstituted isomers (Table 1, entry 4). Aiming to achieve a
better regioselectivity, the protection of 4a−4e with p-nitro-
benzyl bromide (PNBBr) was carried out under the optimized
tritylation reaction conditions, resulting in the formation of the
corresponding p-nitrobenzyl-tetrazole derivatives 6 and 7 in
good overall yield (entries 5−9). The regioselectivity was
dependent on the substituent at the 5-position. Nevertheless,
moderate selectivity for the formation of 1,2-disubstituted-2H-
tetrazoles was observed, starting from β-keto-1H-tetrazoles 4a,
4b, 4c, and 4e. In contrast with this observation, tetrazole 4d
bearing a 1H-indolyl group, afforded 1,5-disubstituted-1H-
tetrazole 6i as the major product (entry 8). The structural
assignment of the N-protected tetrazoles was based on the
analysis of the NOESY spectra of 2H-azirines derived from
tetrazoles 6e and 7e (see below). Moreover, the regioisomeric N-
benzyl and N-(p-nitrobenzyl)tetrazole derivatives can be easily
distinguished by 1H NMR. Isomers 6 always show the methylenic
protons of the tetrazole 5-substituent at higher chemical shifts
than isomers 7, whereas the chemical shift of the methylenic
protons of the protecting group are observed at lower chemical
shifts (see Table S1, Supporting Information). The structural
assignment of the N-protected tetrazoles was also confirmed by
the analysis of the NOESY spectra of 2H-azirines derived from
tetrazoles 6e and 7e (see below). Isomers 6 and 7 were easily
separated by flash chromatography and were used separately in
the following reactions.
Scheme 3. Synthesis of β-Ketoxime-1H-tetrazoles 5
outcome was the same. We were pleased to observed that, when
performing the reaction of 1H-tetrazole 4a with triphenylmethyl
chloride in the presence of triethylamine, in THF at 40 °C for 2
h,17 the expected N-trityl-tetrazoles 6a/7a were obtained in 81%
overall yield. As expected, the N-protection was regioselective,
giving the 2-trityl-2H-tetrazole 7a as the major product (Table 2,
entry 1). Using the same reaction conditions, tritylation of
Table 2. Alkylation of β-Keto-1H-tetrazoles 4
a
entry
β-keto-1H-tetrazole
R2
Tr
overall yield (%)
(6:7)
1
2
3
4
5
6
7
8
9
4a
4c
4e
4a
4a
4b
4c
4d
4e
81
79
90
71
78
77
66
69
74
(18:82)
(10:90)
(18:82)
(50:50)
(40:60)
(37:63)
(43:57)
(60:40)
(46:54)
Tr
Tr
b
Bn
PNB
PNB
PNB
PNB
PNB
β-Keto-1H-tetrazoles 6d−6i and β-keto-2H-tetrazoles 7d−7i
were readily converted into the corresponding ketoximes 8a−8f
and 9a−9f, respectively, by treatment with hydroxylamine
hydrochloride in refluxing EtOH/pyridine for 3 h (Scheme 4).
The target compounds 8 and 9 were obtained in high yields (81−
98%) as a mixture of syn and anti isomers.
a
b
1
Ratio determined by H NMR. Reaction time = 18 h.
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the p-nitrobenzyl group, whereas, for azirines 11b and 11d, no
connectivity was observed between the same protons.
Scheme 4. Synthesis of β-Ketoxime-tetrazoles 8 and 9
In the case of β-ketoximes 9e and 9f, the conversion into the
corresponding 2H-azirines was not so straightforward. Reaction
of 9e with tosyl chloride in the presence of triethylamine for 18 h
did not lead to the desired product, affording only degradation
products. As for of β-ketoxime 9f, after 1.5 h, the TLC control
indicated that there was no more starting material, and due to the
darkening of the reaction mixture, it was stopped. Nevertheless,
after purification by flash chromatography, 2-(2H-tetrazol-5-yl)-
2H-azirine 11e and ketoxime tosylate 12 could be isolated in 4%
and 27% yield, respectively. No reaction was observed when
ketoxime tosylate 12 was treated with triethylamine in
dichloromethane for 24 h. However, the DBU-mediated Neber
reaction of ketoxime tosylate 12 gave the desired product in 23%
yield (Scheme 6).
Scheme 6. Synthesis of 2H-Azirine 11e
The synthesis of 2-(tetrazol-5-yl)-2H-azirines from β-ketox-
ime-tetrazoles via in situ tosylation in the presence of a base was
then explored (Scheme 5). The reaction of β-ketoxime of N-
Scheme 5. Synthesis of 2H-Azirines 10 and 11
We then investigated wether the two alkaloids, quinidine and
quinine, first reported by Zwannenburg and co-workers,5c might
be used effectively in the Neber reaction to achieve an
asymmetric synthesis of 2H-azirine 10b. To our delight,
treatment of ketoxime tosylate 13 with a stoichiometric amount
of quinidine in toluene at 0 °C for 24 h gave a smooth conversion
trityltetrazoles 7a−7c with tosyl chloride in the presence of
triethylamine did not lead to the formation of the corresponding
2H-azirines. These results, although disappointing, were some-
how expected due to the presence of the bulky trityl group.
However, a different outcome was observed when the reaction of
β-ketoxime-tetrazoles 8 and 9 was carried out. To our delight,
treatment of β-ketoxime-1H-tetrazoles 8a−8d with tosyl
chloride and triethylamine in dichloromethane at room temper-
ature for 18 h gave a smooth conversion into the desired 2H-
azirines 10a−10d in yields ranging from 59% to 86%. In a similar
way, β-ketoxime-2H-tetrazoles 9a−9d afforded the correspond-
ing 2H-azirines 11a−11d in good yield (61−77%). From the
reaction of β-ketoximes 9c and 9d, the β-ketoxime tosylate
intermediates were also isolated in low yield (6−7%). The
structural assignment of compounds 10b, 10d, 11b, and 11d was
established based on two-dimensional NOESY experiments. In
the spectra of 10b and 10d, connectivity was observed between
the proton of the 2H-azirine ring and the methylenic protons of
to the desired enriched 2H-azirine 10b′ with 54% ee ([α]D20
=
−146, CH2Cl2, c = 1.3) (Scheme 7). On the other hand, carrying
Scheme 7. Asymmetric Synthesis of 2H-Azirine 10b
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General Procedure for the Preparation of 5-Substituted-1H-
Tetrazoles. Tetrazoles were prepared following the reported
procedure14 with a slight modification. To a pressure tube was added
the nitrile (5.17 mmol), sodium azide (0.37 g, 5.69 mmol), zinc bromide
(1.16 g, 5.17 mmol), water (12 mL), and iPrOH (1.5 mL). The sealed
tube was submerged in an oil bath at 140 °C and stirred vigorously for
the appropriate time. After cooling the tube to room temperature, the
tube was opened, HCl (3 N, 8 mL) and ethyl acetate (25 mL) were
added, and vigorous stirring was continued until no solid was present.
The organic layer was isolated, and the aqueous layer was extracted with
ethyl acetate (2 × 25 mL). The combined organic layers were
evaporated, 50 mL of 0.25 N NaOH was added, and the mixture was
stirred for 30 min, until the original precipitate was dissolved and a
suspension of zinc hydroxide was formed. The suspension was filtered
through Celite, and the Celite pad was washed with 5 mL of 1 N NaOH.
To the filtrate was added 10 mL of 3 N HCl with vigorous stirring,
causing the tetrazole to precipitate. The tetrazole was filtered and dried.
1-Phenyl-2-(1H-tetrazol-5-yl)ethanone) (4a):13c Yield: 76%, 0.74 g,
light yellow solid, mp 178−180 °C (187−188 °C from literature);13c IR
(KBr) 1385, 1450, 1568, 1597, 1684, 2895, 2951, 3028 cm−1; 1H NMR
(400 MHz, DMSO-d6) δ 4.96 (s, 2H), 7.60 (pseudo t, J = 7.6 Hz, 2H),
7.71−7.73 (m, 1H), 8.10 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 34.0, 128.4, 128.9, 134.0, 135.4, 150.8, 193.9; HRMS (ESI,
TOF) calcd for C9H9N4O 189.07709 [MH+], found 189.07693.
1-(Furan-2-yl)-2-(1H-tetrazol-5-yl)ethanone (4b): Yield: 72%, 0.66
g, brown solid, mp 181−183 °C; IR (KBr) 1396, 1464, 1574, 1672,
2854, 2966, 3142 cm−1; 1H NMR (400 MHz, DMSO-d6,) δ 4.71 (s, 2H),
6.80−6.81 (m, 1H), 7.69 (d, J = 3.2 Hz, 1H), 8.11 (br s, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 33.3, 112.9, 120.4, 148.8, 150.7, 181.6; HRMS
(ESI, TOF) calcd for C7H6N4NaO2 201.03830 [MNa+], found
201.03759.
2-(1H-Tetrazol-5-yl)-1-(thiophen-2-yl)ethanone (4c): Yield: 73%,
0.73 g, light brown solid, mp 166−168 °C; IR (KBr) 1328, 1417, 1524,
1560, 1655, 2891, 3007, 3099 cm−1; 1H NMR (400 MHz, DMSO-d6) δ
4.89 (s, 2H), 7.33 (pseudo t, J = 4.4 Hz, 1H), 8.12 (d, J = 4.8 Hz, 1H),
8.19 (d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 34.1, 129.0,
135.0, 136.2, 142.2, 150.5, 186.7; HRMS (ESI,TOF) calcd for
C7H6N4NaOS 217.01545 [MNa+], found 217.01535.
1-(1H-Indol-3-yl)-2-(1H-tetrazol-5-yl)ethanone (4d): Yield: 94%,
1.10 g, light pink solid, mp 223−225 °C; IR (film) 1437, 1520, 1549,
1631, 3055, 3288 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 4.72 (s, 2H),
7.19−7.26 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H),
8.60 (d, J = 2.8 Hz, 1H), 12.36 (br s, N-H); 13C NMR (100 MHz,
DMSO-d6) δ 34.1, 112.4, 115.2, 121.0, 122.1, 123.1, 125.3, 135.4, 136.7,
187.6; HRMS (ESI, TOF) calcd for C11H9N5NaO 250.06993 [MNa+],
found 250.06985.
out the reaction of 13 under the same reaction conditions, but in
the presence of quinine, led to the synthesis of 2H-azirine 10b″ in
good yield, albeit with 44% ee ([α]2D0 = +105, CH2Cl2, c = 1.0).
The enantiomeric purity of 2H-azirines 10b′ and 10b″ was
determined by NMR using Yb(tfc)3 as a chiral shift reagent (20
mg shift reagent vs 20 mg substrate). The determination of
enantiomeric excess was calculated by the ratio of the signals
(two doublets) corresponding to the two aromatic p-nitro-
benzylic protons observed at higher chemical shift. As previously
observed in Zwannenburg’s work, the pseudoenantiomers of the
alkaloid bases gave opposite antipodes of the 2H-azirine 10b.
Correlation with the optical rotation previously reported for
(S)- and (R)-3-phenyl-2H-azirine-2-carboxylates4b allows us to
propose the absolute configuration of 2H-azirines 10b. Thus,
2H-azirine 10b′ is characterized by an optical rotation with a
negative sign, indicating that the use of quinidine leads
predominantly to the R enantiomer. On the other hand, the
quinine-mediated Neber reaction led to 2H-azirine 10b″ having
an optical rotation with a positive sign corresponding to the
selective formation of the S enantiomer.
CONCLUSIONS
■
Synthesis of novel 2-(tetrazol-5-yl)-2H-azirines bearing phenyl,
furan-2-yl, thiophen-2-yl, and pyrrol-2-yl substituents at C-3 via
the Neber reaction of β-ketoxime tetrazole derivatives is
reported. These three-membered heterocyclic compounds can
be particularly interesting as building blocks for the synthesis of
new 5-substituted tetrazoles. Preliminary studies on the
asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines showed
that quinidine- and quinine-mediated Neber reactions lead to
enantioselectivity, being the major enantiomer dependent on the
alkaloid used.
EXPERIMENTAL SECTION
■
NMR spectra were run in CDCl3 or DMSO-d6 on a 400 MHz
instrument and recorded at the following frequencies: proton (1H, 400
MHz), carbon (13C, 100 MHz). Chemical shifts are expressed in parts
per million related to internal TMS and coupling constants (J) are in
hertz. Infrared spectra (IR) were recorded on a Fourier transform
spectrometer. Mass spectra were recorded under electrospray ionization
(ESI). Melting points were determined in open glass capillaries and are
uncorrected. Thin-layer chromatography (TLC) analyses were
performed using precoated silica gel plates. Flash column chromatog-
raphy was performed with silica gel 60 as the stationary phase. Optical
rotations were recorded with a path length of 1 dm, and concentrations,
c, are in g/100 mL. The preparation of 5-substituted-tetrazoles was
carried out in an Ace pressure tube, Bushing type, B (volume ∼ 35 mL).
Nitriles were prepared using general procedures described in the
literature (3a,11 3c,11 3d,12 and 3e12).
1-(1H-Pyrrol-2-yl)-2-(1H-tetrazol-5-yl)ethanone (4e): Yield: 44%,
0.40 g, brown solid, mp 235−237 °C; IR (KBr) 1402, 1443, 1545, 1651,
2713, 2870, 3307 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 4.59 (s, 2H),
6.27 (pseudo t, J = 1.6 Hz, 1H), 7.19−7.22 (m, 2H), 12.02 (br s, N-H);
13C NMR (100 MHz, DMSO-d6) δ 32.8, 110.3, 118.3, 126.8, 130.4,
182.2; HRMS (ESI, TOF) calcd for C7H8N5O 178.07234 [MH+], found
178.07223.
3-Oxo-3-(thiophen-2-yl)propanenitrile (3c). Nitrile 3c was
prepared following the reported procedure11 with a slight modification.
To a solution of acetonitrile (1.0 equiv, 3.5 mmol) in THF (12 mL)
stirred at room temperature was added dropwise a solution of KOt-Amyl
(3.0 equiv, 1.7 M in PhMe), followed by dropwise addition of ethyl
thiophenecarboxylate (3 equiv). After 24 h at room temperature, the
reaction mixture was diluted with 0.25 M HCl (120 mL) and ethyl
acetate (120 mL). The layers were separated, and the organic layer was
washed sequentially with H2O (2 × 50 mL) and brine (2 × 50 mL),
dried over anhydrous Na2SO4, and filtered. The solvent was evaporated
off, affording the corresponding nitrile 3c ,which was recrystallized in
ethyl acetate/hexane. Yield: 70%, 0.37 g, light yellow solid, mp 131−133
°C; IR (KBr) 735, 857, 1232, 1394, 1416, 1516, 1666, 2256, 2951, 3091,
3115 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.00 (s, 2H), 7.20 (t, J = 4.4
Hz, 1H), 7.78−7.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 29.6,
113.5, 128.7, 133.7, 136.3, 140.9, 179.6; HRMS (ESI, TOF) calcd for
C7H6NOS 152.01646 [MH+], found 152.01679.
General Procedure for the Preparation of 2-Trityl-5-Sub-
stituted-2H-tetrazoles. 5-Substituted-1H-tetrazole (10 mmol) was
slurried in THF (12 mL), and Et3N (1.48 mL, 10.5 mmol) was added.
The temperature of the solution was increased to 40 °C, and
triphenylmethyl chloride (10.5 mmol) in THF (6 mL) was added
slowly. The solution was stirred at 40 °C for 5 h, whereupon the mixture
was allowed to cool and the precipitated triethylammonium chloride was
filtered, and washed with cold THF. The solvent was evaporated under
vacuum, giving the crude product as a mixture of the 1,5- and 2,5-
disubstituted isomers. The 2,5-disubstituted isomer 7 was the major
isomer and was isolated by recrystallization in diethyl ether.
2-(1-Trityl-1H-tetrazol-5-yl)-1-phenylethanone (6a) and 2-(2-
Trityl-2H-tetrazol-5-yl)-1-phenylethanone (7a): Yield: 81%, 3.49 g.
6a and 7a were obtained in a (18:82) ratio, and compound 7a was
separated by recrystallization in diethyl ether. 2-(2-Trityl)-2H-tetrazol-5-
yl)-1-phenylethanone (7a): Light yellow solid, mp 142−144 °C; IR
1
(KBr) 698, 756, 1001, 1448, 1493, 1597, 1695, 3061 cm−1; H NMR
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(400 MHz, CDCl3) δ 4.64 (s, 2H), 7.10−7.11 (m, 6H), 7.29−7.35 (m,
9H), 7.44−7.48 (m, 2H), 7.57−7.60 (m, 1H), 7.98 (d, J = 7.6 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 36.6, 83.1, 127.8, 127.9, 128.3, 128.5,
1H NMR (400 MHz, DMSO-d6) δ 5.11 (s, 2H), 5.82 (s, 2H), 7.54−7.61
(m, 4H), 7.70−7.72 (m, 1H), 8.03 (d, J = 7.6 Hz, 2H), 8.22 (d, J = 8.2
Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 33.7, 49.1, 123.7, 128.5,
128.8, 129.4, 134.1, 135.3, 141.9, 147.3, 151.2, 193.5; HRMS (ESI,
TOF) calcd for C16H14N5O3 324.10912 [MH+], found 324.10912.
1-(Furan-2-yl)-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)ethanone (6f)
and 1-(Furan-2-yl)-2-(2-(4-nitrobenzyl)-2H-tetrazol-5-yl)ethanone
(7f): Yield: 77%, 2.41 g. 6f and 7f were obtained in a (37:63) ratio
and separated by flash chromatography [ethyl acetate/hexane (1:1)],
giving by order of elution: 1-(Furan-2-yl)-2-(2-(4-nitrobenzyl)-2H-
tetrazol-5-yl)ethanone (7f): Brown solid, mp 106−108 °C; IR 1344,
1460, 1525, 1566, 1668, 3003 cm−1; 1H NMR (400 MHz, DMSO-d6) δ
4.64 (s, 2H), 6.19 (s, 2H), 6.82−6.83 (m, 1H), 7.65−7.69 (m, 3H), 8.11
(br s, 1H), 8.32 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ
35.0, 54.8, 112.8, 120.2, 124.0, 129.6, 141.2, 147.5, 148.6, 150.9, 160.8,
182.3; HRMS (ESI, TOF) calcd for C14H12N5O4 314.08838 [MH+],
found 314.08911. 1-(Furan-2-yl)-2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-
ethanone (6f): Brown solid, mp 154−156 °C; IR 1345, 1460, 1524, 1661,
128.8, 130.2, 133.5, 136.0, 141.3, 159.8, 193.7; HRMS (ESI, TOF) calcd
for C28H22N4NaO 453.16858 [MNa+], found 453.16766.
2-(1-Trityl-1H-tetrazol-5-yl)-1-(thiophen-2-yl)ethanone (6b) and
2-(2-Trityl-2H-tetrazol-5-yl)-1-(thiophen-2-yl)ethanone (7b): Yield:
79%, 3.45 g. 6b and 7b were obtained in a (10:90) ratio, and compound
7b was separated by recrystallization in diethyl ether. 2-(2-Trityl)-2H-
tetrazol-5-yl)-1-(thiophen-2-yl)ethanone (7b): Light yellow solid, mp
136−138 °C; IR (KBr) 638, 698, 748, 1225, 1416, 1446, 1493, 1668,
3064 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.58 (s, 2H), 7.11−7.14 (m,
7H), 7.30−7.35 (m, 9H), 7.67 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 3.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 37.1, 83.2, 127.8, 128.2, 128.4,
130.2, 133.0, 134.4, 141.2, 142.9, 159.4, 186.3; HRMS (ESI, TOF) calcd
for C26H20N4NaOS 459.12500 [MNa+], found 459.12585.
1-(1H-Pyrrol-2-yl)-2-(1-Trityl-1H-tetrazol-5-yl)ethanone (6c) and
1-(1H-Pyrrol-2-yl)-2-(2-trityl-2H-tetrazol-5-yl)ethanone (7c): Yield:
90%, 3.77 g. 6c and 7c were obtained in a (18:82) ratio, and compound
7c was separated by recrystallization in diethyl ether. 1-(1H-Pyrrol-2-yl)-
2-(2-trityl-2H-tetrazol-5-yl)ethanone (7c): Light yellow solid, mp 122−
124 °C; IR (KBr) 640, 700, 754, 883, 1109, 1275, 1398, 1444, 1639,
1778, 3290 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 4.53 (s, 2H), 6.23−
6.25 (m, 1H), 7.01−7.05 (m, 6H), 7.11−7.13 (m, 1H), 7.15−7.16 (m,
1H), 7.37−7.41 (m, 9H), 11.96 (br s, NH); 13C NMR (100 MHz,
DMSO-d6) δ 35.0, 82.2, 110.1, 118.0, 126.4, 127.9, 128.4, 129.6, 130.6,
140.9, 160.5, 183.2; HRMS (ESI, TOF) calcd for C26H21N5NaO
442.16383 [MNa+], found 442.16368.
General Procedure for the Alkylation of 5-Substituted-1H-
Tetrazoles with Benzyl Bromides. 5-Substituted-1H-tetrazole (10
mmol) was slurried in THF (12 mL), and Et3N (1.48 mL, 10.5 mmol)
was added. The temperature of the solution was increased to 40 °C, and
benzyl bromide or p-nitrobenzyl bromide (10.5 mmol) in THF (6 mL)
was added slowly. The solution was stirred at 40 °C for 2−3 h,
whereupon the mixture was allowed to cool and the precipitate
triethylammonium bromide was filtered and washed with cold THF.
The solvent was evaporated under vacuum, giving the crude product as a
variable mixture of the 1,5- and 2,5-disubstituted isomers, which were
separated by flash chromatography (ethyl acetate/hexane).
1
3005 cm−1; H NMR (400 MHz, DMSO-d6) δ 4.89 (s, 2H), 5.84 (s,
2H), 6.80−6.81 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 3.6 Hz,
1H), 8.09 (br s, 1H), 8.23 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 33.0, 49.2, 112.9, 120.3, 123.7, 129.4, 141.9, 147.3, 148.7,
150.5, 150.6, 181.1; HRMS (ESI, TOF) calcd for C14H12N5O4
314.08838 [MH+], found 314.08828.
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-(thiophen-2-yl)ethanone
(6g) and 2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-1-(thiophen-2-yl)-
ethanone (7g): Yield: 66%, 2.17 g. 6g and 7g were obtained in a
(43:57) ratio and separated by flash chromatography [ethyl acetate/
hexane (1:1)], giving by order of elution: 2-(2-(4-Nitrobenzyl)-2H-
tetrazol-5-yl)-1-(thiophen-2-yl)ethanone (7g): Brown solid, mp 120−122
1
°C; IR 1346, 1416, 1527, 1657, 2980 cm−1; H NMR (400 MHz,
DMSO-d6) δ 4.75 (s, 2H), 6.14 (s, 2H), 7.30 (pseudo t, J = 4.4 Hz, 1H),
7.61 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 3.6 Hz,
1H), 8.26 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 35.7,
54.8, 124.0, 128.9, 129.6, 134.8, 136.0, 141.3, 142.5, 147.5, 161.0, 187.4;
HRMS (ESI, TOF) calcd for C14H11N5NaO3S 352.04748 [MNa+],
found 352.04754. 2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-(thiophen-2-
yl)ethanone (6g): Brown solid, mp 174−176 °C; IR 1346, 1414, 1518,
1655, 2968 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 5.06 (s, 2H), 5.84
(s, 2H), 7.33 (pseudo t, J = 4.4 and 4.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H),
8.12 (d, J = 4.8 Hz, 1H), 8.17 (d, J = 3.6 Hz, 1H), 8.22 (d, J = 8.4 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) 33.6, 49.2, 123.7, 129.0, 129.4,
135.2, 136.3, 141.9, 147.3, 150.8, 186.1; HRMS (ESI, TOF) calcd for
C14H12N5O3S 330.06554 [MH+], found 330.06573.
2-(1-Benzyl-1H-tetrazol-5-yl)-1-phenylethanone (6d) and 2-(2-
Benzyl-2H-tetrazol-5-yl)-1-phenylethanone (7d): Yield: 71%, 1.98 g.
6d and 7d were obtained in a (50:50) ratio and separated by flash
chromatography [ethyl acetate/hexane (1:1)], giving by order of
elution: 2-(2-Benzyl-2H-tetrazol-5-yl)-1-phenylethanone (7d): Yellow
solid, mp 63−65 °C; IR (KBr) 995, 1219, 1396, 1448, 1597, 1705,
2968, 3062 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 4.81 (s, 2H), 5.94
(s, 2H), 7.34−7.42 (m, 5H), 7.55−7.58 (m, 2H), 7.67−7.71 (m, 1H),
8.05 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 35.7, 55.8,
128.2, 128.4, 128.5, 128.8, 133.7, 134.2, 135.7, 161.0, 194.7; HRMS
(ESI, TOF) calcd for C16H15N4O 279.12404 [MH+], found 279.12332.
2-(1-Benzyl-1H-tetrazol-5-yl)-1-phenylethanone (6d): Yellow solid, mp
119−121 °C; IR (KBr) 993, 1217, 1333, 1467, 1599, 1687, 2962, 3070
1-(1H-Indol-3-yl)-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)ethanone
(6h) and 1-(1H-Indol-3-yl)-2-(2-(4-nitrobenzyl)-2H-tetrazol-5-yl)-
ethanone (7h): Yield: 69%, 2.50 g. 6h and 7h were obtained in a
(60:40) ratio and separated by flash chromatography [ethyl acetate/
hexane (2:1)], giving by order of elution: 1-(1H-Indol-3-yl)-2-(2-(4-
nitrobenzyl)-2H-tetrazol-5-yl)ethanone (7h): Light yellow solid, mp
1
181−183 °C; IR 1346, 1428, 1522, 1633, 2950, 3222 cm−1; H NMR
(400 MHz, DMSO-d6) δ 4.59 (s, 2H), 6.14 (s, 2H), 7.19−7.26 (m, 2H),
7.50 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 8.12 (d, J = 7.6 Hz,
1H), 8.27 (d, J = 8.4 Hz, 2H), 8.51 (d, J = 3.2 Hz, 1H), 12.09 (br s, N-H);
13C NMR (100 MHz, DMSO-d6) δ 36.0, 54.8, 112.2, 115.5, 121.1, 122.0,
1
cm−1; H NMR (400 MHz, DMSO-d6) δ 5.07 (s, 2H), 5.64 (s, 2H),
7.31−7.34 (m, 5H), 7.57−7.61 (m, 2H), 7.71−7.74 (m, 1H), 8.05 (d, J =
7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 33.7, 50.0, 128.2, 128.5,
128.7, 128.8, 134.0, 134.5, 135.3, 150.7, 193.4; HRMS (ESI, TOF) calcd
for C16H15N4O 279.12404 [MH+], found 279.12334.
123.0, 124.0, 125.3, 129.6, 135.2, 136.6, 141.4, 147.5, 162.0, 188.6;
HRMS (ESI, TOF) calcd for C18H15N6O3 363.12001 [MH+], found
363.11888. 1-(1H-Indol-3-yl)-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-
ethanone (6h): Light yellow solid, mp 189−191 °C; IR 1346, 1429,
1524, 1633, 2968, 3111, 3419 cm−1; 1H NMR (400 MHz, DMSO-d6) δ
4.94 (s, 2H), 5.91 (s, 2H), 7.24−7.30 (m, 2H), 7.57 (d, J = 8.0 Hz, 1H),
7.62 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 8.4 Hz,
2H), 8.61 (s, 1H), 12.23 (br s, N-H); 13C NMR (100 MHz, DMSO-d6)
δ 33.6, 49.3, 112.3, 115.2, 121.1, 122.1, 123.2, 123.7, 125.2, 129.4, 135.5,
136.6, 142.0, 147.2, 151.6, 187.1; HRMS (ESI, TOF) calcd for
C18H15N6O3 363.12001 [MH+], found 363.11887.
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-phenylethanone (6e) and
2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-1-phenylethanone (7e): Yield:
78%, 2.52 g. 6e and 7e were obtained in a (40:60) ratio and separated by
flash chromatography [ethyl acetate/hexane (1:1)], giving by order of
elution: 2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-1-phenylethanone (7e):
Light yellow solid, mp 112−114 °C; IR (KBr) 1352, 1518, 1597,
1691, 2958 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 4.83 (s, 2H), 6.15
(s, 2H), 7.55−7.61 (m, 4H), 7.68−7.71 (m, 1H), 8.05 (d, J = 7.6 Hz,
2H), 8.27 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 36.6,
54.9, 124.0, 128.8, 129.5, 133.8, 135.6, 147.5, 161.3, 194.6; HRMS (ESI,
TOF) calcd for C16H14N5O3 324.10912 [MH+], found 324.10920. 2-(1-
(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-phenylethanone (6e): Light yellow
solid, mp 192−194 °C; IR (KBr) 1350, 1518, 1597, 1676, 1691, 2968;
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-(1H-pyrrol-2-yl)ethanone
(6i) and 2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-1-(1H-pyrrol-2-yl)-
ethanone (7i): Yield: 74%, 2.31 g. 6i and 7i were obtained in a
(46:54) ratio and separated by flash chromatography [ethyl acetate/
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hexane (2:1)], giving by order of elution: 2-(2-(4-Nitrobenzyl)-2H-
tetrazol-5-yl)-1-(1H-pyrrol-2-yl)ethanone (7i): Brown solid, mp 141−
143 °C; IR 1344, 1394, 1518, 1643, 3372 cm−1; 1H NMR (400 MHz,
DMSO-d6) δ 4.46 (s, 2H), 6.13 (s, 2H), 6.24 (br s, 1H), 7.15 (br s, 2H),
7.61 (d, J = 8.4 Hz, 2H), 8.26 (d, J = 8.4 Hz, 2H), 11.94 (br s, N-H); 13C
NMR (100 MHz, DMSO-d6) δ 34.7, 54.8, 110.1, 118.1, 123.9, 126.5,
129.5, 130.7, 141.3, 147.5, 161.7, 183.1; HRMS (ESI, TOF) calcd for
C14H12N6NaO3 335.08631 [MNa+], found 335.08675. 2-(1-(4-Nitro-
benzyl)-1H-tetrazol-5-yl)-1-(1H-pyrrol-2-yl)ethanone (6i): Brown solid,
mp 221−222 °C; IR 1348, 1396, 1514, 1641, 3411 cm−1; 1H NMR (400
MHz, DMSO-d6) δ 4.79 (s, 2H), 5.84 (s, 2H), 6.28 (br s, 1H), 7.18 (br s,
1H), 7.24 (br s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 8.4 Hz, 2H),
12.00 (br s, N-H); 13C NMR (100 MHz, DMSO-d6) δ 32.4, 49.2, 110.3,
118.6, 123.7, 126.9, 129.3, 130.2, 142.0, 147.2, 151.3, 181.7; HRMS
(ESI, TOF) calcd for C14H13N6O3 313.10436 [MNa+], found
313.10347.
General Procedure for the Preparation of Oximes 8 and 9.
Tetrazoles 6 or 7 (3.5 mmol) were dissolved in a mixture of ethanol/
pyridine (1:1) (10 mL), and hydroxylamine hydrochloride (3 equiv,
10.5 mmol, 0.73 g) was added. The reaction mixture was heated under
reflux for 3 h. The solvent was evaporated under reduced pressure, and
the crude substrate was dissolved in cold water (20 mL) and extracted
with ethyl acetate (3 × 25 mL). The combined organic layers were dried
over anhydrous Na2SO4 and filtered, and the solvent was evaporated off,
affording the corresponding oximes, which were recrystallized in diethyl
ether.
2-(1-Benzyl-1H-tetrazol-5-yl)-1-phenylethanone oxime (8a):
Yield: 87%, 0.89 g, white solid, mp 142−144 °C; IR (KBr) 1066,
1109, 1288, 1493, 1514, 3037, 3207 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 4.42 (s, 2H), 5.72 (s, 2H), 7.28−7.30 (m, 2H), 7.38−7.40 (m, 6H),
7.61−7.63 (m, 2H), 11.83 (br s, OH); 13C NMR (100 MHz, DMSO-d6)
δ 19.8, 49.8, 126.0, 127.9, 128.3, 128.4, 128.8, 129.1, 134.4, 134.9, 150.4,
152.1; HRMS (ESI) calcd for C16H16N5O 294.13494 [MH+], found
294.13415.
2-(2-Benzyl-2H-tetrazol-5-yl)-1-phenylethanone oxime (9a):
Yield: 89%, 0.91 g, white solid, mp 99−101 °C; IR (KBr) 970, 1273,
1444, 1489, 2931, 3068 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 4.37
(s, 2H), 5.85 (s, 2H), 7.22−7.24 (m, 2H), 7.33−7.37 (m, 6H), 7.66−
7.67 (m, 2H), 11.57 (br s, OH); 13C NMR (100 MHz, DMSO-d6) δ
21.9, 55.6, 126.0, 128.0, 128.3, 128.4, 128.7, 128.9, 134.2, 135.4, 151.4,
162.7; HRMS (ESI) calcd for C16H16N5O 294.13494 [MH+], found
294.13413.
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-phenylethanone oxime
(8b): Yield: 84%, 1.00 g, white solid, mp 172−174 °C; IR (KBr)
1348, 1417, 1510, 1525, 1608, 3217 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 4.34 (s, 2H), 5.91 (s, 2H), 7.37−7.39 (m, 3H), 7.50 (d, J = 8.8 Hz,
2H), 7.64−7.66 (m, 2H), 8.24 (d, J = 8.4 Hz, 2H), 11.76 (br s, OH); 13C
NMR (100 MHz, DMSO-d6) δ 19.9, 49.0, 123.8, 126.0, 128.4, 129.0,
129.1, 134.9, 141.8, 147.3, 150.4, 152.6; HRMS (ESI, TOF) calcd for
C16H15N6O3 339.12001 [MH+], found 339.12065.
2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-1-phenylethanone oxime
(9b): Yield: 83%, 0.98 g, white solid, mp 138−140 °C; IR (KBr)
1348, 1489, 1525, 1612, 2857, 3242 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 4.38 (s, 2H), 6.06 (s, 2H), 7.36−7.37 (m, 3H), 7.47 (d, J = 8.4 Hz,
2H), 7.66−7.67 (m, 2H), 8.21 (d, J = 8.4 Hz, 2H), 11.58 (br s, OH); 13C
NMR (100 MHz, DMSO-d6) δ 21.9, 54.6, 123.8, 126.0, 128.3, 128.8,
129.2, 134.4, 141.4, 147.4, 151.4, 163.0; HRMS (ESI, TOF) calcd for
C16H15N6O3 339.12001 [MH+], found 339.12082.
1-(Furan-2-yl)-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)ethanone
oxime (8c): Yield: 81%, 0.93 g, light brown solid, mp 136−138 °C; IR
(KBr) 951, 1111, 1352, 1460, 1525, 1610, 2858, 3161 cm−1; 1H NMR
(400 MHz, DMSO-d6) δ 4.32 and 4.38 (s, 2H), 5.87 and 5.91 (s, 2H),
6.58 and 6.64 (br s, 1H), 6.84 (d, J = 2.8 Hz) and 7.33 (d, J = 3.2 Hz),
7.49−7.56 (m, 2H), 7.70 and 7.72 (br s, 1H), 8.24 (d, J = 8.4 Hz, 2H),
11.68 and 11.77 (br s, OH); 13C NMR (100 MHz, DMSO-d6) δ 19.8
and 25.4, 49.0, 110.4, 111.7, 112.3, 117.2, 123.8, 129.0, 129.3, 140.2,
141.8, 143.0 and 143.1, 144.2 and 144.6, 147.3, 149.0, 152.4 and 152.8;
HRMS (ESI, TOF) calcd for C14H13N6O4 329.09928 [MH+], found
329.09876.
1-(Furan-2-yl)-2-(2-(4-nitrobenzyl)-2H-tetrazol-5-yl)ethanone
oxime (9c): Yield: 93%, 1.07 g, light brown solid, mp 124−126 °C; IR
1
(KBr) 986, 1198, 1348, 1514, 1606, 3149, 3440 cm−1; H NMR (400
MHz, DMSO-d6) δ 4.19 and 4.23 (s, 2H), 6.09 (s, 2H), 6.55 (pseudo t, J
= 1.2 Hz, 1H) and 6.62 (pseudo t, J = 1.6 Hz, 1H), 6.79 (d, J = 3.2 Hz)
and 7.34 (d, J = 3.2 Hz), 7.50−7.54 (m, 2H), 7.70 and 7.71 (br s, 1H),
8.24 (d, J = 8.4 Hz, 2H), 11.51 and 11.72 (br s, OH); 13C NMR (100
MHz, DMSO-d6) δ 28.0, 54.7, 110.0, 111.6, 112.1, 117.0, 123.9, 129.2
and 129.3, 141.2 and 141.5, 142.9, 143.9, 145.0, 147.4, 163.8; HRMS
(ESI, TOF) calcd for C14H13N6O4 329.09928 [MH+], found 329.09955.
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-(thiophen-2-yl)ethanone
oxime (8d): Yield: 96%, 1.16 g, white solid, mp 164−167 °C; IR (KBr)
1
951, 1350, 1425, 1470, 1527, 1601, 2845, 2989, 3147 cm−1; H NMR
(400 MHz, DMSO-d6) δ 4.45 (s, 2H), 5.91 (s, 2H), 7.07 (pseudo t, J =
4.4 Hz and J = 4.0 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H), 7.48 (d, J = 8.4 Hz,
2H), 7.52 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 8.4 Hz, 2H), 11.70 (br s, OH);
13C NMR (100 MHz, DMSO-d6) δ 20.4, 49.0, 123.8, 127.3, 127.4, 127.5,
128.9, 138.8, 141.8, 146.7, 147.3, 152.3; HRMS (ESI, TOF) calcd for
C14H13N6O3S 345.07644 [MH+], found 345.07683.
2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-1-(thiophen-2-yl)ethanone
oxime (9d): Yield: 94%, 1.13 g, white solid, mp 133−138 °C; IR (KBr)
1
964, 1340, 1435, 1493, 1527, 1612, 2951, 3111, 3236 cm−1; H NMR
(400 MHz, DMSO-d6) δ 4.33 and 4.37 (s, 2H), 6.09 (s, 2H), 7.05
(pseudo t, J = 4.4 Hz and J = 4.0 Hz, 1H) and 7.11 (pseudo t, J = 4.4 Hz),
7.36 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.53 (d, J = 8.4 Hz,
2H), 7.75 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 8.4 Hz, 2H), 11.50 and 12.01
(br s, OH); 13C NMR (100 MHz, DMSO-d6) δ 22.4 and 29.8, 54.7,
123.9, 125.6, 127.0, 127.3, 129.1, 129.3, 129.4, 130.6, 130.9, 139.4, 141.4,
144.7, 147.4 and 147.8, 162.7 and 162.8; HRMS (ESI, TOF) calcd for
C14H13N6O3S 345.07644 [MH+], found 345.07687.
1-(1H-Indol-3-yl)-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)ethanone
oxime (8e): Yield: 98%, 1.29 g, light yellow solid, mp 197−200 °C; IR
(KBr) 1103, 1348, 1406, 1437, 1524, 1595, 1608, 3128, 3263 cm−1; 1H
NMR (400 MHz, DMSO-d6) δ 446 (s, 2H), 5.91 (s, 2H), 7.03 (pseudo
t, J = 7.2 Hz and J = 7.6 Hz, 1H), 7.15 (pseudo t, J = 7.6 Hz and J = 7.2
Hz, 1H), 7.38−7.43 (m, 3H), 7.77 (s,1H), 7.99 (d, J = 8.0 Hz, 1H), 8.12
(d, J = 8.4 Hz, 2H), 11.12 (br s, N-H), 11.40 (br s, OH); 13C NMR (100
MHz, DMSO-d6) δ 20.7, 48.9, 111.4, 111.6, 119.9, 122.2, 123.7, 123.9,
124.2, 127.2, 128.7, 136.1, 136.8, 141.9, 147.1, 148.1, 149.6, 153.2;
HRMS (ESI, TOF) calcd for C18H16N7O3 378.13091 [MH+], found
378.13240.
1-(1H-Indol-3-yl)-2-(2-(4-nitrobenzyl)-2H-tetrazol-5-yl)ethanone
oxime (9e): Yield: 94%, 1.24 g, light yellow solid, mp 193−195 °C; IR
(KBr) 906, 1340, 1439, 1495, 1518, 1612, 3076, 3246 cm−1; 1H NMR
(400 MHz, DMSO-d6) δ 4.35 (s, 2H), 6.05 (s, 2H), 7.06 (pseudo t, J =
7.2 Hz and J = 7.6 Hz, 1H), 7.15 (pseudo t, J = 7.6 Hz and J = 7.2 Hz,
1H), 7.39 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.72 (s,1H), 8.11
(d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.4 Hz, 2H), 10.82 (br s, N-H), 11.34 (br
s, OH); 13C NMR (100 MHz, DMSO-d6) δ 22.8, 54.6, 111.5, 112.0,
119.8, 122.1, 122.4, 123.9, 124.4, 126.9, 129.2, 136.8, 141.5, 147.4, 149.3,
163.8; HRMS (ESI, TOF) calcd for C18H16N7O3 378.13091 [MH+],
found 378.13216.
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-(1H-pyrrol-2-yl)ethanone
oxime (8f): Yield: 90%, 1.03 g, light yellow oil; IR (film) 987, 1111, 1348,
1419, 1522, 1608, 3215, 3427 cm−1; 1H NMR (400 MHz, DMSO-d6) δ
4.28 and 4.32 (s, 2H), 5.80 and 5.87 (s, 2H), 6.06 and 6.13 (br s, 1H),
6.41 and 6.59 (br s, 1H), 6.79 and 6.92 (br s, 1H), 7.44−7.50 (m, 2H),
8.19−8.22 (m, 2H), 11.01 and 11.30 (br s, N-H), 11.07 and 11.34 (br s,
OH); 13C NMR (100 MHz, DMSO-d6) δ 20.2 and 26.2, 49.2, 107.9,
108.3, 110.3, 112.8, 121.1, 121.8, 123.4, 123.7, 123.8, 128.9, 129.3, 141.4,
141.8, 141.9, 144.4, 147.2, 152.9; HRMS (ESI, TOF) calcd for
C14H14N7O3 328.11526 [MH+], found 328.11521.
2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-1-(1H-pyrrol-2-yl)ethanone
oxime (9f): Yield: 92%, 1.05 g, light yellow solid, mp 160−162 °C; IR
(KBr) 985, 1111, 1348, 1433, 1525, 1610, 3124, 3419 cm−1; 1H NMR
(400 MHz, DMSO-d6) δ 4.09 and 4.19 (s, 2H), 6.03−6.09 (m, 3H), 6.35
and 6.48 (br s, 1H), 6.77 and 6.89 (br s, 1H), 7.55 (d, J = 8.4 Hz, 2H),
8.24 (d, J = 8.4 Hz, 2H), 10.85 and 11.01 (br s, N-H), 11.29 (br s, OH);
13C NMR (100 MHz, DMSO-d6) δ 22.2 and 28.9, 54.7, 107.7, 108.2,
109.7, 112.5, 120.6, 121.3, 123.8, 123.9, 127.2, 129.3, 129.4, 141.4, 141.5,
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142.6, 145.5, 147.5, 163.4 and 164.1; HRMS (ESI, TOF) calcd for
C14H14N7O3 328.11526 [MH+], found 328.11469.
2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-3-(thiophen-2-yl)-2H-azir-
ine (11d): Yield: 66%, 0.22 g, light brown solid, mp 119−121 °C; IR
(KBr) 1332, 1457, 1563, 1607, 1742, 3074, 3111 cm−1; 1H NMR (400
MHz, DMSO-d6) δ 3.68 (s, 1H), 6.10 (s, 2H), 7.42 (pseudo t, J = 4.4 Hz
and J = 4.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 2.8 Hz, 1H),
8.26 (d, J = 8.4 Hz, 2H), 8.33 (d, J = 4.8 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 24.9, 54.9, 124.0, 124.4, 129.3, 129.6, 136.3, 136.9, 141.1,
147.5, 153.7, 166.3; HRMS (ESI, TOF) calcd for C14H11N6O2S
327.06587 [MH+], found 327.06525.
Synthesis of 5-(3-(1H-pyrrol-2-yl)-2H-azirin-2-yl)-2-(4-nitro-
benzyl)-2H-tetrazole (11e). 2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-
(1H-pyrrol-2-yl)ethanone O-Tosyl Oxime (12). To a solution of oxime
9f (1.0 mmol, 0.33 g) in dichloromethane (20 mL), at 0 °C under a
nitrogen atmosphere, was added triethylamine (1.3 equiv) and tosyl
chloride (1.2 equiv, 1.2 mmol, 0.23 g). The mixture was allowed to warm
at room temperature, and the reaction mixture was monitored by TLC.
After 1.5 h, there was no evidence of oxime and the reaction mixture was
isolated. The solvent was evaporated under vacuum, and the crude
reaction was dissolved in ethyl acetate (20 mL) and washed with water
(3 × 10 mL). The organic layer was dried over anhydrous MgSO4 and
filtered, and the solvent was evaporated under vacuum. The crude
product was purified by flash chromatography [ethyl acetate/hexane
(1:1)], giving by order of elution: O-tosyl oxime (12, 27%, 0.13 g) and
2H-azirine 11e (4%, 12 mg). Data for compound 12: light brown oil; 1H
NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 4.27 (s, 2H), 6.10 (s, 2H),
6.26 (pseudo d, J = 1.2 Hz, 1H), 6.92 (br s, 1H), 7.15 (br s, 1H), 7.40 (d,
J = 8.0 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 8.23
(d, J = 8.4 Hz, 2H), 11.5 (br s, N-H); 13C NMR (100 MHz, DMSO-d6) δ
21.1, 28.5, 54.7, 110.0, 118.9, 120.1, 123.9, 125.3, 128.3, 129.2, 129.7,
131.8, 141.4, 145.2, 147.4, 151.3, 162.3; HRMS (ESI, TOF) calcd for
C21H19N6O5S2 499.08529 [MH+], found 499.08502.
3-(1H-Pyrrol-2-yl)-2-(2-(4-nitrobenzyl)-2H-tetrazol-5-yl)-2H-azir-
ine (11e). To a solution of oxime 12 (0.25 mmol, 0.12 g) in
dichloromethane (5 mL), at room temperature under a nitrogen
atmosphere, was added DBU (1.3 equiv). The mixture was monitored
by TLC, and after 2 h, there was no evidence of oxime. The solvent was
evaporated under vacuum, and the crude reaction was dissolved in ethyl
acetate (20 mL) and washed with water (3 × 10 mL). The organic layer
was dried over anhydrous MgSO4 and filtered, and the solvent was
evaporated under vacuum. The crude product was purified by flash
chromatography [ethyl acetate/hexane (1:1)]. Yield: 23%, 18 mg, light
brown oil; 1H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 1H), 6.09 (s, 2H),
6.45 (br s, 1H), 6.97 (br s, 1H), 7.49 (br s, 1H), 7.62 (d, J = 7.2 Hz, 2H),
8.34 (d, J = 6.8 Hz, 2H), 12.59 (br s, N-H); 13C NMR (100 MHz,
DMSO-d6) δ 20.2, 49.1, 111.4, 114.3, 119.1, 124.0, 128.0, 128.9, 142.1,
147.4, 148.5, 155.9; HRMS (ESI, TOF) calcd for C14H12N7O2
310.10470 [MH+], found 310.10448.
General Procedure for the Preparation of oximes 5. Tetrazoles
4a or 4c (3.5 mmol) were dissolved in a mixture of ethanol/pyridine
(1:1) (10 mL), and hydroxylamine hydrochloride (3 equiv, 10.5 mmol)
was added. The reaction mixture was heated under reflux for 3 h. The
solvent was evaporated under reduced pressure, and cold water (20 mL)
and ice (10 g) were added, causing the oximes to precipitate. The oximes
were filtered and recrystallized in diethyl ether.
General Procedure for the Synthesis of 2H-Azirines 10a−10d
and 11a−11d. To a solution of oxime 8 or 9 (1.0 mmol) in
dichloromethane (20 mL), at 0 °C under a nitrogen atmosphere, was
added triethylamine (1.3 equiv) and tosyl chloride (1.2 equiv). The
mixture was allowed to warm at room temperature, and the reaction
mixture was stirred for 12 h. The solvent was evaporated under vacuum,
and the crude reaction was dissolved in ethyl acetate (20 mL) and
washed with water (3 × 10 mL). The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evaporated under
vacuum. The crude product was purified by flash chromatography (ethyl
acetate/hexane).
2-(1-Benzyl-1H-tetrazol-5-yl)-3-phenyl-2H-azirine (10a): Yield:
63%, 0.17 g, yellowish oil; IR (film) 1319, 1452, 1520, 1605, 1755,
2854, 2927 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.27 (s, 1H), 5.62 (d, J
= 15.6 Hz, 1H), 5.74 (d, J = 15.6 Hz, 1H), 7.22−7.26 (m, 2H), 7.31−
7.33 (m, 3H), 7.51−7.54 (m, 2H), 7.61−7.65 (m, 1H), 7.77 (d, J = 7.6
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 22.3, 51.2, 122.2, 127.5, 128.9,
129.2, 129.4, 130.5, 133.7, 134.3, 154.2, 161.4; HRMS (ESI) calcd for
C16H14N5 276.12437 [MH+], found 276.12364.
2-(2-Benzyl-2H-tetrazol-5-yl)-3-phenyl-2H-azirine (11a): Yield:
77%, 0.21 g, yellow solid, mp 83−85 °C; IR (KBr) 1277, 1450, 1504,
1597, 1749, 3028 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.53 (s, 1H),
5.69 (s, 2H), 7.34−7.36 (m, 5H), 7.55−7.58 (m, 2H), 7.62−7.65 (m,
1H), 7.92−7.94 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.0, 56.8,
123.0, 128.5, 129.0, 129.3, 130.3, 133.1, 133.7, 160.9, 167.0; HRMS
(ESI) calcd for C16H14N5 276.12437 [MH+], found 276.12360.
3-Phenyl-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-2H-azirine (10b):
Yield: 86%, 0.28 g, white solid, mp 130−132 °C; IR (KBr) 1348,
1450, 1522, 1605, 1757, 2938, 3066 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 3.84 (s, 1H), 6.16 (s, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.70−7.71 (m,
2H), 7.72−7.74 (m, 1H), 7.96 (d, J = 7.2 Hz, 2H), 8.34 (d, J = 8.4 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) δ 21.3, 49.2, 121.7, 124.1, 129.0,
129.7, 130.3, 134.4, 142.0, 147.4, 155.5, 159.5; HRMS (ESI, TOF) calcd
for C16H13N6O2 321.10945 [MH+], found 321.10991.
3-Phenyl-2-(2-(4-nitrobenzyl)-2H-tetrazol-5-yl)-2H-azirine (11b):
Yield: 73%, 0.23 g, white solid, mp 124−126 °C; IR (KBr) 1348,
1521, 1605, 1757, 3068, 3199 cm−1; 1H NMR (400 MHz, DMSO-d6) δ
3.68 (s, 1H), 6.13 (s, 2H), 7.63−7.65 (m, 2H), 7.71−7.74 (m, 2H),
7.79−7.81 (m, 1H), 8.01 (d, J = 7.2 Hz, 2H), 8.30 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 24.0, 54.9, 122.3, 124.0, 129.6, 129.7,
130.0, 134.1, 141.1, 147.5, 160.3, 166.6; HRMS (ESI, TOF) calcd for
C16H13N6O2 321.10945 [MH+], found 321.10895.
3-(Furan-2-yl)-2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-2H-azirine
(10c): Yield: 59%, 0.18 g, brown solid, mp 146−148 °C; IR (KBr) 1417,
1524, 1560, 1661, 2891, 3007, 3111 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 3.84 (s, 1H), 6.09 (s, 2H), 6.92 (d, J = 1.6 Hz, 1H), 7.57−7.60 (m,
3H), 8.29 (d, J = 8.4 Hz, 2H), 8.34 (br s,1H); 13C NMR (100 MHz,
DMSO-d6) δ 21.2, 49.2, 113.6, 123.4, 124.1, 129.0, 138.4, 141.9, 147.4,
149.1, 151.2, 155.0; HRMS (ESI, TOF) calcd for C14H11N6O3
311.08871 [MH+], found 311.08852.
3-(Furan-2-yl)-2-(2-(4-Nitrobenzyl)-2H-tetrazol-5-yl)-2H-azirine
(11c): Yield: 61%, 0.19 g, light brown solid, mp 112−114 °C; IR (KBr)
1348, 1466, 1522, 1608, 1759, 3008, 3134 cm−1; 1H NMR (400 MHz,
DMSO-d6) δ 3.70 (s, 1H), 6.15 (s, 2H), 6.96 (d, J = 1.6 Hz, 1H), 7.64−
7.68 (m, 3H), 8.31 (d, J = 8.4 Hz, 2H), 8.37 (br s,1H); 13C NMR (100
MHz, DMSO-d6) δ 23.8, 55.0, 113.5, 122.6, 124.0, 129.6, 139.0, 141.1,
147.5, 150.0, 150.8, 166.1; HRMS (ESI, TOF) calcd for C14H11N6O3
311.08871 [MH+], found 311.08840.
1-Phenyl-2-(1H-tetrazol-5-yl)ethanone oxime (5a): Yield: 83%,
0.59 g, white solid, mp 176−178 °C; IR (KBr) 690, 748, 972, 1065,
1286, 1412, 1441, 1495, 1570, 1896, 2598, 2885, 3230 cm−1; 1H NMR
(400 MHz, DMSO-d6) δ 4.37 (s, 2H), 7.40−7.41 (m, 3H), 7.72−7.74
(m, 2H), 11.73 (br s, OH); 13C NMR (100 MHz, DMSO-d6) δ 20.4,
126.0, 128.4, 129.0, 135.2, 150.8; HRMS (ESI, TOF) calcd for
C9H10N5O 204.08799 [MH+], found 204.08759.
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-3-(thiophen-2-yl)-2H-azir-
ine (10d): Yield: 70%, 0.23 g, light brown solid, mp 144−146 °C; IR
(KBr) 1344, 1412, 1522, 1610, 1751, 3076, 3126 cm−1; 1H NMR (400
MHz, DMSO-d6) δ 3.90 (s, 1H), 6.15 (s, 2H), 7.48 (pseudo t, J = 4.4 Hz,
1H), 7.65 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 2.8 Hz, 1H), 8.35 (d, J = 8.8
Hz, 2H), 8.41 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
22.3, 49.2, 123.5, 124.1, 129.0, 129.4, 136.8, 137.6, 142.0, 147.4, 152.9,
155.2; HRMS (ESI, TOF) calcd for C14H11N6O2S 327.06587 [MH+],
found 327.06562.
2-(1H-Tetrazol-5-yl)-1-(thiophen-2-yl)ethanone oxime (5c): Yield:
77%, 0.56 g. 5c was obtained as a mixture of isomers (15:85). White
solid, mp 173−175 °C; IR (KBr) 692, 851, 960, 1016, 1072, 1263, 1321,
1410, 1433, 1558, 1606, 2889, 3007, 3213 cm−1; Major isomer: 1H NMR
(400 MHz, DMSO-d6) δ 4.37 (s, 2H), 7.09 (pseudo t, J = 4.4 Hz, 1H),
7.44 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 4.4 Hz, 1H), 11.63 (br s, OH); 13C
NMR (100 MHz, DMSO-d6) δ 20.8, 127.3, 127.4, 131.2, 139.1, 147.2;
1
Minor isomer: H NMR (400 MHz, DMSO-d6) δ 4.42 (s, 2H), 7.16
(pseudo t, J = 4.4 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 4.4 Hz,
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1H), 12.12 (br s, OH); 13C NMR (100 MHz, DMSO-d6) δ 27.8, 125.7,
129.1, 130.5, 144.0, 152.4; HRMS (ESI, TOF) calcd for C7H8N5OS
210.04441 [MH+], found 210.04452.
Liang, C.-H.; Venkat Reddy, G.; Zhang, Y.; Fang, T.; Titus, D. D. J. Org.
Chem. 1999, 64, 8929−8935. (d) Davis, F. A.; Deng, J. Org. Lett. 2007, 9,
1707−1710.
2-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-1-phenylethanone O-Tosyl
Oxime (13). To a solution of oxime 8b (0.34 g, 1.0 mmol, 1 equiv) in
THF (5 mL) at 0 °C were added p-toluenesulfonic chloride (1 equiv)
and K2CO3 (2 equiv). The reaction mixture was stirred at room
temperature for 24 h. The resulting mixture was then filtered, and the
solvent was evaporated off and purified by flash chromatography [ethyl
acetate/hexane (1:2)]. Yield: 39%, 0.19 g, white solid, mp 141−143 °C;
1H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 4.35 (s, 2H), 5.74 (s, 2H),
7.28−7.30 (m, 6H), 7.31−7.35 (m, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.81
(d, J = 8.0 Hz, 2H), 8.15 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 21.8, 22.3, 50.1, 124.4, 128.3, 128.9, 129.0, 130.0, 130.8 131.4,
139.7, 146.2, 148.2, 150.1, 158.9; HRMS (ESI, TOF) calcd for
C23H21N6O5S 493.12886 [MH+], found 493.12886.
General Procedure for the Asymmetric Synthesis of 2H-
Azirines 10b′ and 10b″.5c To a stirred solution of alkaloid base (1
equiv) in toluene (45 mL), a solution of ketoxime tosylate 13 (100 mg,
0.2 mmol) in toluene (5 mL) was added dropwise at 0 °C. The reaction
mixture was stirred at 0 °C for 24 h, whereupon aqueous HCl (0.05M,
25 mL) was added. The resulting mixture was extracted with ethyl
acetate (3 × 25 mL), and the combined organic layers were washed with
brine, dried over anhydrous MgSO4, and filtered. The solvent was
evaporated under vacuum. The crude product was purified by flash
chromatography [ethyl acetate/hexane (1:1)].
(-)-3-Phenyl-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-2H-azirine
(10b′). Following the general procedure, using quinidine, 13 gave, after
workup and purification, 10b′ as a white solid (40.4 mg, 0.126 mmol).
Yield: 63% (54% ee); [α]2D0 = −146 (CHCl3, c = 1.3).
(5) (a) Neber, P. W.; Friedolsheim, A. Justus Liebigs Ann. Chem. 1926,
449, 109−134. (b) Neber, P. W.; Burgard, A.; Their, W. Justus Liebigs
Ann. Chem. 1936, 526, 277−294. (c) Verstappen, M. M. H.; Ariaans, G.
J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491−8492.
(d) Skepper, C. K.; Dalisay, D. S.; Molinski, T. F. Org. Lett. 2008, 10,
5269−5271. (e) Skepper, C. K.; Dalisay, D. S.; Molinski, T. F. Bioorg.
Med. Chem. Lett. 2010, 20, 2029−2032. (f) Palacios, F.; Ochoa de
Retana, A. M.; Gil, J. I.; Ezpeleta, J. M. J. Org. Chem. 2000, 65, 3213−
3217. (g) Palacios, F.; Aparicio, D.; Retana, A. M. O.; de los Santos, J.
M.; Gil, J. I.; Munain, R. L. Tetrahedron: Asymmetry 2003, 14, 689−700.
(h) Sakamoto, S.; Inokuma, T.; Takemoto, Y. Org. Lett. 2011, 13, 6374−
6377.
́ ́ ́
(6) Roh, J.; Vavrova, K.; Hrabaleck, A. Eur. J. Org. 2012, 6101−6118.
(7) Lodyga-Chruscinska, E. Coord. Chem. Rev. 2011, 255, 1824−1833.
(8) (a) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147−3176.
(b) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529−2591.
(9) (a) Pinho e Melo, T. M. V. D.; Rocha Gonsalves, A. M. d’A.; Lopes,
C. S. J.; Gilchrist, T. L. Tetrahedron Lett. 1999, 40, 789−792. (b) Pinho e
Melo, T. M. V. D.; Lopes, C. S. J.; Cardoso, A. L.; Rocha Gonsalves, A.
M. d’A. Tetrahedron 2001, 57, 6203−6208. (c) Rocha Gonsalves, A. M.
d’A.; Cabral, A. M. T. D. P. V.; Pinho e Melo, T. M. V. D.; Gilchrist, T. L.
Synthesis 1997, 673−676.
(10) (a) Lopes, S. M. M.; Brigas, A. F.; Palacios, F.; Lemos, A.; Pinho e
Melo, T. M. V. D. Eur. J. Org. Chem. 2012, 2152−2160. (b) Lopes, S. M.
M.; Lemos, A.; Pinho e Melo, T. M. V. D. Tetrahedron Lett. 2010, 51,
6756−6759. (c) Lopes, S. M. M.; Palacios, F.; Lemos, A.; Pinho e Melo,
T. M. V. D. Tetrahedron 2011, 67, 8902−8909.
(+)-3-Phenyl-2-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)-2H-azirine
(10b″). Following the general procedure, using quinine, 13 gave, after
workup and purification, 10b″ as a white solid (47.4 mg, 0.148 mmol).
Yield: 74% (44% ee); [α]2D0 = +105 (CHCl3, c = 1.0).
(11) Ji, Y.; Trenkle, W. C.; Vowles, J. V. Org. Lett. 2006, 8, 1161−1163.
(12) Slatt, J.; Romero, I.; Bergman, J. Synthesis 2004, 16, 2760−2765.
̈
(13) (a) Arnold, C., Jr.; Thatcher, D. N. J. Org. Chem. 1969, 34, 1141−
1142. (b) Matthews, D. P.; Green, J. E.; Shuker, A. J. J. Comb. Chem.
́
2000, 2, 19−23. (c) Fetter, J.; Nagy, I.; Giang, L. T.; Kajtar-Peredy, M.;
ASSOCIATED CONTENT
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Rockenbauer, A.; Korecz, L.; Czira, G. J. Chem. Soc., Perkin Trans. 1
2001, 1131−1139.
S
* Supporting Information
1H and 13C NMR spectra of all new compounds and NOESY
spectra of compounds 10b, 10d, 11b, and 11d. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945−7950.
(15) Chao, S.-J.; Hui, X.-P.; Li, S.; Qiu, Z.-Z.; Xu, P.-F.; Zhang, Z.-Y.;
Wang, Q. J. Chin. Chem. Soc. 2005, 52, 539−544.
(16) (a) Huff, B. E.; LeTourneau, M. E.; Staszak, M. A.; Ward, J. A.
Tetrahedron Lett. 1996, 37, 3655−3658. (b) Myznikov, L. V.;
Artamonova, T. V.; Bel’skii, V. K.; Stash, A. I.; Skvortsov, N. K.;
Koldobskii, G. I. Russ. J. Org. Chem. 2002, 38, 1360−1369.
(17) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.;
Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D.
M.; Verhoeven, T. R.; Reider, P. J. Org. Chem. 1994, 59, 6391−6394.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tmelo@ci.uc.pt.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Thanks are due to Fundaca
̧
o para a Cien
̃
̂
cia e a Tecnologia (PEst-
C/QUI/UI0313/2011 and SFRH/BPD/34569/2007) for fi-
nancial support. We acknowledge the Nuclear Magnetic
Resonance Laboratory of the Coimbra Chemistry Center
(www.nmrccc.uc.pt), University of Coimbra, for obtaining the
NMR data.
REFERENCES
■
(1) (a) Palacios, F.; Retana, A. M. O.; Marigueta, E. M.; Santos, J. M.
Eur. J. Org. Chem. 2001, 2401−2414. (b) Pinho e Melo, T. M. V. D.;
Rocha Gonsalves, A. M. d’A. Curr. Org. Synth. 2004, 1, 275−292.
(c) Lemos, A. Molecules 2009, 14, 4098−4119. (d) Padwa, A. Adv.
Heterocycl. Chem. 20010, 99, 1−31.
(2) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971, 24, 48−
50.
(3) Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103−2105.
(4) (a) Legters, J.; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas
1992, 111, 75−78. (b) Gentilucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg,
B. Tetrahedron Lett. 1995, 36, 4665−4668. (c) Davis, F. A.; Liu, H.;
6991
dx.doi.org/10.1021/jo4006552 | J. Org. Chem. 2013, 78, 6983−6991